N-Methyl-l-leucyl-l-leucine hydro­chloride monohydrate

Tao Lu; Mu-Wu Xu; Xiao-Jian Liao; Shi-Hai Xu

doi:10.1107/S1600536811031126

. 2011 Aug 27;67(Pt 9):o2394. doi: 10.1107/S1600536811031126

N-Methyl-l-leucyl-l-leucine hydrochloride monohydrate

Tao Lu ^a, Mu-Wu Xu ^b,^*, Xiao-Jian Liao ^a, Shi-Hai Xu ^a

PMCID: PMC3200702 PMID: 22058991

Abstract

In the title compound C₁₃H₂₇N₂O₃ ⁺·Cl⁻·H₂O, obtained by deprotecting the amino and carboxyl groups of an intermediate in the synthesis of the cyclic pentapeptide Galaxamide, a number of hydrogen-bonding interactions occur including aminium N—H⋯Cl, amide–carboxyl N—H⋯O, water O—H⋯Cl and carboxyl–water O—H⋯O associations. The aminium N—H⋯Cl⋯H—N bridging extensions give rise to zigzag chains extending along the a axis, the overall two-dimensional structure lying in the (110) plane.

Related literature

For general background to peptides, see: Humphrey & Chamberlin (1997 ▶). For the synthesis of Galaxamide, see: Xu, Liao, Xu et al. (2008 ▶); Rodriguez et al. (2007 ▶). For related structures, see: Liao et al. (2007 ▶); Xu, Liao, Diao et al. (2008 ▶).

Experimental

Crystal data

C₁₃H₂₇N₂O₃ ⁺·Cl⁻·H₂O
M _r = 312.83
Monoclinic,
a = 5.2212 (2) Å
b = 9.6032 (5) Å
c = 18.4081 (8) Å
β = 96.329 (4)°
V = 917.36 (7) Å³
Z = 2
Mo Kα radiation
μ = 0.22 mm⁻¹
T = 295 K
0.45 × 0.32 × 0.17 mm

Data collection

Oxford Diffraction Xcalibur Sapphire3 Gemini Ultra CCD diffractometer
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2011 ▶) T _min = 0.990, T _max = 1.000
3703 measured reflections
2616 independent reflections
2271 reflections with I > 2sI)
R _int = 0.015

Refinement

R[F ² > 2σ(F ²)] = 0.042
wR(F ²) = 0.114
S = 1.01
2616 reflections
186 parameters
1 restraint
H-atom parameters constrained
Δρ_max = 0.37 e Å⁻³
Δρ_min = −0.22 e Å⁻³
Absolute structure: Flack (1983 ▶), 686 Friedel pairs
Flack parameter: −0.01 (8)

Data collection: CrysAlis PRO (Agilent, 2011 ▶); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: OLEX2 (Dolomanov et al., 2009 ▶); software used to prepare material for publication: OLEX2.

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536811031126/zs2126sup1.cif

e-67-o2394-sup1.cif^{(19.2KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536811031126/zs2126Isup2.hkl

e-67-o2394-Isup2.hkl^{(125.8KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536811031126/zs2126Isup3.cml

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1A⋯Cl1ⁱ	0.90	2.31	3.174 (2)	161
N1—H1B⋯Cl1	0.90	2.25	3.092 (2)	155
N2—H2⋯O2ⁱⁱ	0.86	2.40	3.006 (3)	128
O3—H3A⋯O4	0.85	1.74	2.591 (5)	179
O4—H4A⋯Cl1ⁱⁱⁱ	0.85	2.51	3.198 (4)	139
O4—H4B⋯Cl1^iv	0.85	2.48	3.182 (4)	141

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) ; (iv) .

Acknowledgments

This work was supported by grants from the National High Technology Development Project (863 Project, No. 2006 A A09Z408), the National Natural Science Fund (No. 20772048), the Tianhe Science and Technology Plan Project (No. 104zh134), and the Fundamental Research Funds for the Central Universities (Nos. 21611412 and 21611382)

supplementary crystallographic information

Comment

Peptide compounds play an important role in life activities (Humphrey & Chamberlin, 1997). The title compound C₁₃H₂₇N₂O₃⁺ Cl^- . H₂O (Fig. 1) is a modified dipeptide employed in the synthesis of the cytotoxic cyclic pentapeptide Galaxamide (Xu, Liao, Xu et al., 2008), obtained by deprotecting the amino and carboxyl groups of the intermediate (Rodriguez et al., 2007). The purpose was to explore the activity targets of the intermediates in relation to those of the target compound (Liao et al., 2007, Xu, Liao, Diao et al., 2008). In the crystal structure of the title compound, there are a number of intermolecular hydrogen-bonding interactions (Table 1), including aminium N—H···Cl, amide N—H···O_carboxyl, water O—H···Cl and carboxylic acid O—H···O_water associations. The aminium N—H···Cl···H—N bridging extensions give zigzag chains extending along the a axis in the unit cell, the overall two-dimensional structure lying along (110) (Fig 2).

Experimental

Diisopropylethylamine (DIPEA) (6 mmol, 1.1 ml) was added dropwise to a stirred solution of L-leucine benzyl ester p-toluenesulfonate (6 mmol, 2.36 g) in anhydrous THF (8 ml) at 273 K under nitrogen and stirred for 15 min. The coupling reagent DEPBT (6 mmol, 1.8 g) was added to a stirred solution of N-Boc-Me—L-Leu-OH (5 mmol, 1.30 g) in anhydrous THF (5 ml) at 273 K under nitrogen and the suspension was stirred for 15 min. A suspension of L-leucine benzyl ester p-toluenesulfonate was added by cannula to the N-Boc-Me—L-Leu-OH suspension at 273 K under nitrogen and the mixture was allowed to warm to room temperature over the course of 24 h, then evaporated in vacuo. The crude product was then purified by chromatography on silica using n-hexane/acetone (20:1) as eluent to give the dipeptide as colorless crystals (yield 2.1g: 92.5%). This dipeptide (4 mmol, 1.8 g) was dissolved in CH₂Cl₂ (7 ml) and 2 ml of TFA was added dropwise at 273 K under nitrogen using a constant pressure funnel. The mixture was stirred at 273 K until the starting material disappeared (monitored by TLC). The solution was concentrated in vacuo, the residue was dissolved in CH₂Cl₂2 and concentrated again to remove the Boc dipeptide derivative which was dried in vacuo. This Boc derivative (3 mmol, 1.91 g) was reduced with hydrogen (0.1 Mpa) and 10% Pd—C (0.62 g) in ethyl acetate (40 ml) until the starting material disappeared (monitored using TLC). The Pd—C was filtered, and the filtrate was concentrated in vacuo to obtain the title compound (yield 1.85 g: 97%). Colourless crystals suitable for X-ray analysis grew over a period of a week from a solution in methanol containing a small amount of dilute HCl, when exposed to air.